Affiliations: [a] Faculty of Pharmacy, Laval University, Quebec (QC), Canada | [b] Centre Hospitalier de l'Université Laval (CHUL) Research Center, Quebec (QC), Canada | [c] Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Correspondence:
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Correspondence to: Dr. Frédéric Calon, Centre Hospitalier de l'Université Laval (CHUL) Research Center, Room TR-72, 2705 Laurier Blvd, Quebec, QC, Canada. G1V 4G2; Tel.: +418 654 2296 or +418 656 4141 x48697; Fax: +(418) 654 2761; E-mail: [email protected].
Abstract: Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-β (Aβ) and tau pathology and improves cognitive performance in animal models of Alzheimer's disease (AD). To exclude confounding variables associated with the diet, we crossed 3 × Tg-AD mice (modeling AD neuropathology) with transgenic Fat-1 mice that express the fat-1 gene encoding a PUFA desaturase, which endogenously produces n-3 PUFA from n-6 PUFA. The expression of fat-1 shifted the n-3:n-6 PUFA ratio upward in the brain (+11%, p < 0.001), including docosahexaenoic acid (DHA; +5%, p < 0.001) in 20 month-old mice. The expression of fat-1 decreased the levels of soluble Aβ42 (−41%, p < 0.01) at 20 months without reducing the level of insoluble forms of Aβ40 and Aβ42 in the brain of 3 × Tg-AD mice. The 3 × Tg-AD/Fat-1 mice exhibited lower cortical levels of both soluble (−25%, p < 0.05) and insoluble phosphorylated tau (−55%, p < 0.05) compared to 3 × Tg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3 × Tg-AD/Fat-1 mice (−039%, p < 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3β, cyclin-dependent kinase 5, or protein phosphatase type 2A enzymatic activity. In addition, the expression of the fat-1 transgene prevented the increase of glial fibrillary acidic protein (−37%, p < 0.01) observed in 20 month-old 3 × Tg-AD mice. In conclusion, the expression of fat-1 in 3 × Tg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology.
